The recent development of B cell-depleting/inactivating monoclonal antibodies has revolutionized B cell Non-Hodgkin's Lymphoma (B-NHL) therapy. Although B cell- targeting significantly slows diffuse large B cell lymphoma (DLBCL) progression in patients with low international prognostic index scores, the lifespan of high-risk patients (with more severe/disseminated disease) is not significantly extended. Improving upon existing lymphoma therapies will require extensive analysis of disease etiology in appropriate preclinical model systems. However, existing B lymphoma models have been described predominantly as endpoints in the definition of tumor suppressor genes or oncogenes, and not utilized to evaluate common cellular/molecular aspects of lymphoma progression and response to treatment. We have developed a novel murine model, which conditionally lacks PTEN and SHIP inositol phosphatases in B lymphocytes and develops lethal lymphoma with 100% penetrance within one year. Interestingly, bPten/Ship-/- B cells display abnormal mitogenic responses to the B cell survival factor BAFF. Although our preliminary studies defining SHIP as a tumor suppressor have potential diagnostic/prognostic utility, the experiments outlined in this proposal will utilize bPten/Ship-/- mice to identify in vivo factors that are important for DLBCL progression and likely independent of the initial lymphomagenic insult. We will determine whether lymphomagenesis requires auto-antigen recognition and/or BAFF encounter. Analysis of lymphoma progression in primary model systems will allow us to compare the pathogenicity and sensitivity to B cell targeted therapy of metastatic (lung/liver resident) and secondary lymphoid lymphoma cells. Parallel studies of PI3K regulation will be examined in human DLBCL and MCL. The studies proposed here are highly novel, timely, and necessary for the development of next-generation lymphoma treatments. PUBLIC HEALTH RELEVANCE: B cell lymphoma is a prevalent disease and is represented by the transformation of normal B lymphocytes at definitive stages of development. Although the genetic basis of some B lymphoma types has been identified, the molecular basis of lymphomagenesis and progression is not well understood. In this work, we have developed a novel mouse model to investigate the factors driving B lymphoma.